Vaccines to control tuberculosis in cattle.

The age-old cattle disease has resisted rigorous control, but the BCG vaccine may do better.

BCG vaccination reduces bovine tuberculosis transmission, improving prospects for elimination.

Bacillus Calmette-Guérin (BCG) is a routinely used vaccine for protecting children against Mycobacterium tuberculosis that comprises attenuated Mycobacterium bovis. BCG can also be used to protect livestock against M. bovis; however, its effectiveness has not been quantified for this use. We performed a natural transmission experiment to directly estimate the rate of transmission to and from vaccinated and unvaccinated calves over a 1-year exposure period. The results show a higher indirect efficacy of BCG to reduce transmission from vaccinated animals that subsequently become infected [74%; 95% credible interval (CrI): 46 to 98%] compared with direct protection against infection (58%; 95% CrI: 34 to 73%) and an estimated total efficacy of 89% (95% CrI: 74 to 96%). A mechanistic transmission model of bovine tuberculosis (bTB) spread within the Ethiopian dairy sector was developed and showed how the prospects for elimination may be enabled by routine BCG vaccination of cattle.

Contribution of herd management, biosecurity, and environmental factors to the risk of bovine tuberculosis in a historically low prevalence region.

Eradication of bovine tuberculosis (bTB) in certain historically low-prevalence regions remains elusive. A complete characterisation of the husbandry practices, biosecurity, and environment where farms are located is crucial to implement targeted in-farm risk mitigation protocols. Here, a detailed survey performed in 94 dairy cattle farms located in Navarra, a low-prevalence region of Spain between 2016 and 2020 was carried out. Data on 73 biosecurity, farm-, and environmental-level factors potentially associated with the risk of bTB occurrence were evaluated using an ordinal logistic regression model: farms were classified based on their prevalence index, a score linked to each farm to account for the severity and recurrence of bTB cases: 22.3% of the farms had a score of 1, 21.3% a score of 2, 26.6% a score of ≥ 3, and 29.8% were negative herds. A statistically significant association between a higher prevalence index and the frequency of badger sightings along with the lease of pastures to sheep during Winter was identified. Farms that detected badgers on a monthly to daily basis in the surroundings and those that leased pastures for sheep flocks during Winter were four [odds ratio, 95% CI (4.3; 1.1-17.5)] and three (3.1; 1.0-9.9) times more likely to have the highest prevalence index, respectively (predicted probabilityprevalence index≥3 = 0.7; 95% CI 0.3-0.9). Conversely, farms that used a vehicle to transport animals from holdings to pastures were less likely (0.1; <0.1-0.3) to present higher levels of prevalence index compared with farms that used none (on foot). Results suggested that the combined effect of farm- and environmental-level risk factors identified here may be hampering disease eradication in Navarra, highlighting the need to implement targeted protocols on farms and grazing plots. An increased awareness of monitoring sheep and wildlife in direct or indirect contact with cattle herds in historically low bTB prevalence areas should be raised.

Difference in differences analysis evaluates the effects of the badger control policy on bovine tuberculosis in England.

Persistent tuberculosis (TB) in cattle populations in England has been associated with an exchange of infection with badgers (Meles meles). A badger control policy (BCP) commenced in 2013. Its aim was to decrease TB incidence in cattle by reducing the badger population available to provide a wildlife reservoir for bovine TB. Monitoring data from 52 BCP intervention areas 200-1600 km2 in size, starting over several years, were used to estimate the change in TB incidence rate in cattle herds, which was associated with time since the start of the BCP in each area. A difference in differences analysis addressed the non-random selection and starting sequence of the areas. The herd incidence rate of TB reduced by 56% (95% Confidence Interval 41-69%) up to the fourth year of BCP interventions, with the largest drops in the second and third years. There was insufficient evidence to judge whether the incidence rate reduced further beyond 4 years. These estimates are the most precise for the timing of declines in cattle TB associated with interventions primarily targeting badgers. They are within the range of previous estimates from England and Ireland. This analysis indicates the importance of reducing transmission from badgers to reduce the incidence of TB in cattle, noting that vaccination of badgers, fertility control and on farm biosecurity may also achieve this effect.

Live attenuated Mycobacterium bovis strains combined with the encapsulated H65 antigen as a vaccine strategy against bovine tuberculosis in a mouse model.

Mycobacterium bovis is an etiological agent of bovine tuberculosis (bTB) that also infects other mammals, including humans. The lack of an effective vaccine for the control of bTB highlights the need for developing new vaccines. In this study, we developed and evaluated an M. bovis strain deleted in the virulence genes phoP, esxA and esxB as a vaccine candidate against bTB in BALBc mice. The evaluated strains were the new live vaccine and BCG, alone or in combination with ncH65vD. The immunogen ncH65vD is a fusion protein H65, encapsulated together with vitamin D3, within the oily body of a nanocapsule composed of an antigen-loading polymeric shell. All vaccines conferred protection against the M. bovis challenge. However, no significant differences were detected among the vaccinated groups regarding bacterial loads in lungs and spleen. Mice vaccinated with the mutant strain plus ncH65vD showed negative Ziehl Neelsen staining of mycobacteria in their lungs, which suggests better control of bacteria replication according to this protection parameter. Consistently, this vaccination scheme showed the highest proportion of CD4 + T cells expressing the protection markers PD-1 and CXCR3 among the vaccinated groups. Correlation studies showed that PD-1 and CXCR3 expression levels in lung-resident CD4 T cells negatively correlated with the number of colony forming units of M. bovis in the lungs of mice. Therefore, the results suggest a link between the presence of PD-1 + and CXCR3 + cells at the site of the immune response against mycobacteria and the level of mycobacterial loads.

Wildlife vaccination strategies for eliminating bovine tuberculosis in white-tailed deer populations.

Many pathogens of humans and livestock also infect wildlife that can act as a reservoir and challenge disease control or elimination. Efficient and effective prioritization of research and management actions requires an understanding of the potential for new tools to improve elimination probability with feasible deployment strategies that can be implemented at scale. Wildlife vaccination is gaining interest as a tool for managing several wildlife diseases. To evaluate the effect of vaccinating white-tailed deer (Odocoileus virginianus), in combination with harvest, in reducing and eliminating bovine tuberculosis from deer populations in Michigan, we developed a mechanistic age-structured disease transmission model for bovine tuberculosis with integrated disease management. We evaluated the impact of pulse vaccination across a range of vaccine properties. Pulse vaccination was effective for reducing disease prevalence rapidly with even low (30%) to moderate (60%) vaccine coverage of the susceptible and exposed deer population and was further improved when combined with increased harvest. The impact of increased harvest depended on the relative strength of transmission modes, i.e., direct vs indirect transmission. Vaccine coverage and efficacy were the most important vaccine properties for reducing and eliminating disease from the local population. By fitting the model to the core endemic area of bovine tuberculosis in Michigan, USA, we identified feasible integrated management strategies involving vaccination and increased harvest that reduced disease prevalence in free-ranging deer. Few scenarios led to disease elimination due to the chronic nature of bovine tuberculosis. A long-term commitment to regular vaccination campaigns, and further research on increasing vaccines efficacy and uptake rate in free-ranging deer are important for disease management.

Vaccination of calves with Bacillus Calmette-Guerin Danish strain 1331 results in a duration of immunity of at least 52 weeks.

Bacillus Calmette-Guérin (BCG) Danish strain 1331 (CattleBCG) is currently the lead vaccine candidate for the control of bovine tuberculosis (TB) in cattle in GB, where prior vaccination has shown to result in a significant reduction in bovine TB pathology induced by infection with Mycobacterium bovis (M. bovis). A critical knowledge gap in our understanding of CattleBCG is the duration of immunity post vaccination at the minimum intended vaccine dose. To this end, we performed an experiment where calves were vaccinated with a targeted dose of 106 CFU and, after a period of 52 weeks, experimentally infected with M. bovis. Post mortem examination performed 13 weeks after infection revealed a statistically significant reduction in the severity of TB pathology in the CattleBCG vaccinated group compared with the unvaccinated control group. Additionally, this study allowed us to further assess the diagnostic performance of a defined antigen DIVA reagent (DST-F) developed to detect infected amongst vaccinated animals. Our results demonstrate that when used in a skin test format, DST-F showed high specificity (100 %) in BCG-vaccinated animals when tested prior to infection, whilst detecting all infected animals when re-tested after infection. Furthermore, we also present results supporting the use of the DST-F reagent in an interferon-gamma release assay. In conclusion, the results of this study demonstrate a 52-week duration of immunity following administration of a minimum dose of CattleBCG. This evidence will be a fundamental component in our efforts to apply for UK marketing authorisation to enable vaccination of cattle as a significant additional control measure in the ongoing fight against bovine TB in GB.

Improving the communication between farmers and veterinarians to enhance the acceptability of bovine tuberculosis eradication programmes.

France and Spain have been fighting against bovine tuberculosis (bTB) for years, even though new outbreaks continue to appear on both sides of the border, generating misconceptions about the disease and social distrust in the eradication programme and competent authorities. The perceived disease risk and the commitment of all interested parties are key factors for the successful implementation of control programmes, as they might influence the acceptability of recommended measures. Effective communication can contribute to increasing knowledge, trust and stakeholders' engagement, thus ensuring the acceptability of the eradication programme. This study was conducted in Catalonia (Spain) and Pyrenees-Atlantiques (France) in the frame of the INNOTUB project (https://innotub.eu/) to characterise the communication on bTB in the trans-Pyrenees region and provide recommendations to improve it. The communication on bTB was characterised by analysing 153 (Spain) and 66 (France) online freely available texts, published between 2018 and 2020, through Content Analysis and Critical Metaphor Analysis. Moreover, six farmers and four veterinarians were in-depth interviewed in each area to gather information about the communication on bTB. Interviews were made in original languages and analysed using a qualitative thematic approach. A pilot participatory intervention inspired by the Systematic Tool for Behavioural Assumption Validation and Exploration (STAVE) method was used to develop a list of proposals to improve communication and to promote the creation of territorial networks/committees on bTB prevention and control. It included three focus groups with farmers and veterinarians, a meeting with representatives of the regional veterinary services, and a final deliberative workshop. Results highlight the existence of a controversial debate on bTB and a heterogeneous understanding between stakeholders. Institutional and scientific communication mainly focus on bTB detection and control while other aspects are left in the background. On the contrary, farmers extend their communication to a greater variety of topics. The metaphorical framing strongly differed among actors, while veterinary services and researchers "fight" against bTB and "progress" toward the eradication, farmers place themselves in a framework of "sacrifice" and, particularly in Spain, they play a passive role. The proposals developed by the participants to improve the current communication on bTB included: (i) create participatory meeting spaces to share opinions and information; (ii) improve data accessibility (on epidemiological situations); (iii) develop clearer and written protocols and informative visual material; (iv) redesign the training courses (v) increase the stakeholders' participation in the design of protocols.